DESCRIPTION Directed cell crawling is essential for nerve distribution in embryonic development, the migration of keratinocytes across a wound site, the pursuit and elimination of foreign particles by neutrophils, and the invasion of cancerous cells into healthy tissue. The proposed research is an integrative computational model of intracellular signaling coupled to cytoskeletal reorganization and active force generation in crawling cells The long-term goal is to develop a better understanding of how an external chemoattractant gradient is transduced into an internal signal that coordinates the understanding of how an external chemoattractant gradient is transduced into an internal signal that coordinates the polarized rearrangement and activation of the actin cytoskeleton. The specific aim during the course of the fellowship is to apply and enhance computational technique previously developed by the applicant to specific biological systems. Inputs into the computational model will be micron- scale-averaged interpretations of known chemical and mechanical events at the molecular level. The model output will be the polarization, deformation and resulting locomotion of the stimulated cell, which will be compared to available experimental data on cell shape change and chemotaxis. The well-studied model organism Dictyostelium discoideum will be used to validate the computational model. At this point the model will be modified to study mammalian cells, such as human neutrophils and keratinocytes. It may then be determined whether existing theories of signaling to the cytoskeleton are sufficient to produce the experimentally observed behavior of these crawling cells. The model may also be used to identify a minimal set of signaling mechanisms that suffice to produce motion similar to that observed in living cells.